Phase I clinical trials involving in vivo transplantation or ex vivo exposure to swine tissues or cells are underway. Since all pigs carry in their genome endogenous retroviruses, called porcine endogenous retrovirus or PERV, these xenotransplantation procedures carry the risk of exposure and transmission to PERV. We have previously shown that activation of this normally latent retrovirus occurs after exposure of pig primary peripheral blood mononuclear cells (PBMC) to mitogenic agents. We now have shown that after in vitro passaging of pig PBMC-derived PERV through a human cell line that variants of PERV are selected with enhanced replication properties on the human cell line. This has important implications about cross-species transmission and possible adaptation of PERV to a human host in the xenotransplantation setting. In addition, we have extended our analysis of the porcine plasma-derived product, Hyate:C (porcine factor VIII). We now have shown that porcine plasma carries infectious PERV that was isolated from plasma of 6/6 NIH mini pigs. In this study, we were able to demonstrate that although the porcine plasma carried the coding sequences for all three envelope classes, PERV-A, B, and C (A and B have been shown to be responsible for the human tropism), only the pig-tropic PERV-C virus could be isolated in the culture assay. Finally, we have started to investigate an animal model to study PERV infection properties in vivo through a collaboration with Dan Salamon at The Scripps Institute. Using the NOD/SCID mouse, we have demonstrated in vivo transmission of PERV from porcine pancreatic islets embedded onto RGD templates to 293 cells implanted onto RGD templates at distal sites in the mouse, as well as transmission of PERV to some murine tissues. This is the first published demonstration of in vivo infectivity and replication of PERV.